Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)

NCT ID: NCT01354613

Last Updated: 2019-04-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-04-30
• Study Completion Date: 2013-12-31

Brief Summary

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases in the United States, affecting a primarily elderly population. No treatment has been shown to affect mortality in HFpEF, which is more than 50% at five years a hospitalization. This project explores the underlying cardiovascular physiology of patients with HFpEF with the goal of identifying new therapeutic targets that would allow improved treatment of this devastating disease.

Detailed Description

Heart failure with preserved ejection fraction (HFpEF) is a difficult disease to diagnose due to nonspecific symptoms and clinical findings. The disease occurs in the elderly, who often have other illnesses and signs of aging that make diagnosis of heart failure more difficult. Recently, it has been suggested that HFpEF, which has primarily been thought to be a diastolic disease, is in fact multifactorial, with elements of abnormal systolic function and increased vascular stiffness playing a role in disease pathology. No treatment has been shown to reduce the high mortality of the disease. However, few studies have evaluated this population of patients during periods of increased physiologic stress, despite the consistent clinical presentation of impaired exercise tolerance with few symptoms at rest. This study explores the multifactorial physiology of HFpEF, with a detailed investigation of the specificity of abnormalities in contractile reserve and vascular stiffness for this disease, and exploration of the modifiability of these abnormalities. The techniques used are non-invasive, involving echocardiographic evaluation of cardiac function, and measurement of arterial stiffness using tonometry. The first aim of the study is to explore the specificity of a potential diagnostic test for HFpEF by investigating the change in ejection fraction before and after β-adrenergic stimulation with low-dose dobutamine in HFpEF compared to other groups important to distinguish clinically, specifically patients with shortness of breath due to pulmonary disease, and those with hypertension and left ventricular hypertrophy without clinical heart failure. In the second aim, the study will investigate the ability of the calcium channel blocker, amlodipine, to restore normal contractile responses of the myocardium. In the third aim, the role of arterial stiffness in drug responses in HFpEF will be explored. It is anticipated that improved understanding of the complex physiology of this multifactorial disease gained through this study will lead to more rational design of large clinical trials studying promising agents for HFpEF that impact not only diastolic function, but contractile reserve and arterial properties as well.

Conditions

Heart Failure With Preserved Ejection Fraction; Pulmonary Disease; Left Ventricular Hypertrophy/Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

HFpEF

25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF \> 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will receive amlodipine, oral administration for a period of 12 weeks.

Group Type: EXPERIMENTAL

Dobutamine

Intervention Type: DRUG

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

Amlodipine

Intervention Type: DRUG

Participants will be randomized to treatment with either amlodipine 5 mg daily or placebo, in double-blind fashion, 25 patients in each group. 12 week oral administration of 5mg/day, uptitrated to 10mg/day, determined by PI.

Pulmonary Disease

20 patients with pulmonary disease and no clinical evidence of cardiovascular disease

Group Type: EXPERIMENTAL

Dobutamine

Intervention Type: DRUG

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

LVH/HTN

20 subjects with known left ventricular hypertrophy and clinically diagnosed hypertension without the diagnosis of heart failure.

Group Type: EXPERIMENTAL

Dobutamine

Intervention Type: DRUG

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

HFpEF placebo

25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF \> 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will be administered a placebo for a period of 12 weeks.

Group Type: PLACEBO_COMPARATOR

Dobutamine

Intervention Type: DRUG

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

Interventions

Dobutamine

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

Intervention Type: DRUG

Amlodipine

Participants will be randomized to treatment with either amlodipine 5 mg daily or placebo, in double-blind fashion, 25 patients in each group. 12 week oral administration of 5mg/day, uptitrated to 10mg/day, determined by PI.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Male or female; Age 18 or older.
• Left ventricular ejection fraction ≥ 50%.
• Symptomatic heart failure or appropriate comparator group criteria
• Informed consent signed by the subject

Exclusion Criteria

• Symptoms of active ischemia.
• Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency.
• Serum creatinine > 3.0 or chronic hemodialysis.
• Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 3.0 times the upper limit of normal as read at the local lab.
• Severe renal dysfunction, i.e. glomerular filtration rate (GFR) <30 ml/min.
• Atrial fibrillation
• Myocardial infarction within the last year
• Coronary bypass surgery within the last 6 months
• Stroke within the last 6 months
• Known aortic aneurysm
• Contra-indication to withdrawal of beta blocker or antihypertensive medications
• Resting or orthostatic hypotension (SBP < 90 mmHg)
• Any gastrointestinal disorder which would interfere with drug absorption
• Any significant valvular heart disease, including prior multiple valve replacement.
• Pericardial Disease
• Infiltrative or hypertrophic cardiomyopathy
• Cor pulmonale
• Unstable coronary disease
• Pregnancy
• Any condition which may prevent the subject from adhering to the study protocol, as determined by the investigator

Heart Failure with Preserved Ejection Fraction

• Clinical evidence of heart failure with preserved ejection fraction, as manifest by at least 2 symptoms or signs, including dyspnea on exertion or at rest, orthopnea, jugular venous distention or hepatojugular reflux, rales or edema.
• Controlled systolic BP (< 150 mmHg on the day of study)

Pulmonary Disease Group

• Known obstructive airways disease with objective documentation of an isolated obstructive defect by pulmonary function testing.
• No history of heart failure.
• No history of cardiovascular disease, with the exception of hypertension or hyperlipidemia
• History and physical examination free of signs and symptoms of heart failure, including elevated jugular venous pressure, hepatojugular reflux, rales or edema.
• Baseline echocardiographic examination without evidence of heart failure, including systolic dysfunction of the LV or RV, or evidence of more than mild diastolic dysfunction on non-invasive assessment.

HTN/LVH Group

• Known history of hypertension.
• Echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction.
• No history or physical examination evidence of heart failure, including excessive dyspnea on exertion, dyspnea at rest, orthopnea, PND, jugular venous distention, hepatojugular reflux, rales or edema.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nancy K Sweitzer, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UW-Madison

Locations

UW - Madison

Madison, Wisconsin, United States

Countries

United States

Other Identifiers

R21HL106103-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

H-2010-0061

Identifier Type: -

Identifier Source: org_study_id